Although combination antiretroviral therapy (ART) has been successful in suppressing plasma HIV RNA levels in infected patients, it has not resulted in eradication of virus. It is now clear that prolonged, continuous ART results in significant toxicities and adherence to drug regimens is difficult. In addition, the cost of HAART drugs is prohibitive for many countries and individuals. Therefore, we have studied the virologic and immunologic effects of intermittent versus continuous ART in HIV-infected individuals in an attempt to reduce the total time an individual receives therapy while maintaining therapeutic efficacy. Ongoing studies include a randomized, controlled trial of long cycle intermittent ART (1 month off ART followed by 2 months on ART for 22months) pilot studies of short cycle intermittent ART (7 days off ART followed by 7 days on ART for up to 52 months) and randomized, controlled trials in the U.S. and Uganda of short cycle intermittent versus continuous ART for the treatment of chronic HIIV infection. Following 4-7 cycles of long cycle intermittent therapy, 19 of 22 patients had detectable plasma viremia after each of the 1 month off-drug periods. There was no significant difference in the mean plasma HIV RNA level between the 1st and the 4th cycles off drugs. However, all patients had a viral load of < 500 copies/ml following each of the 2 months on-drug periods; 70% of patients have plasma HIV RNA of < 50 copies/ml after the on-ART periods. Genetic characterization of rebounding plasma HIV RNA revealed that 9 of 12 patients undergoing at least 7 cycles of ART had diverse HIV envelope populations from the first cycle to at least one subsequent cycle. The substantial genetic changes in HIV envelope did not correlate with a log increase or decrease in levels of plasma HIV RNA suggesting that genetic diversity in HIV envelope populations does not contribute in a systemic way to changes in levels of rebounding HIV RNA during long-cycle intermittent therapy. Immunologic analysis indicated that, while there was a transient decrease in the mean CD4+ T cell count during each of the off-HAART periods, the mean CD4+ T cell count returns to the pre-interruption level following 4 weeks on-ART with each cycle. Furthermore, 4 of 8 patients receiving efavirenz-based regimens developed new genotypic and phenotypic resistance to efavirenz following 4-6 cycles of long cycle intermittent ART. Finally, although there was a significant reduction in serum lipid levels at 40 weeks of long cycle intermittent therapy (at the end of the 4th off-ART period), by week 48, following 8 weeks on-HAART there was no significant reduction in these markers of toxicity compared to patients who received continuous therapy. Thus, there is a lack of clear therapeutic benefit in terms of virologic and immunologic effects, as well as of multiple parameters of toxicity, in patients with chronic HIV infection who receive at least 48 weeks of long-cycle intermittent therapy. More importantly, efavirenz, and other non-nucleoside reverse transcriptase inhibitors cannot be recommended for use in long cycle intermittent ART strategies due to the increased risk of developing resistance to these agents. In a previous study, we demonstrated that patients receiving short cycle intermittent therapy (7 days on ART with a dual protease inhibitor-based, twice per day regimen followed by 7 days off) maintained suppression of plasma HIV viremia while reducing serum lipid levels. However, adherence to a twice-a-day regimen is difficult. Thus, we are currently investigating a proof-of?concept study consisting of short cycle intermittent ART with once per day regimen of didanosine, lamivudine and efavirenz in chronically infected patients. Major findings in this study include sustained suppression of plasma HIV RNA of <50 copies in 7 patients for 60 to 84 weeks, preservation of CD4+ T cell counts and no emergence of resistance to antiretroviral drugs. Thus, short cycle intermittent ART may be an important option for the treatment of HIV infection to reduce cost and possibly toxicity while potentially enhancing adherence. This is an especially important strategy for use in resource-limited settings. In this regard, we are conducting a randomized, controlled trial of two short cycle intermittent therapy approaches versus continuous ART in Kampala, Uganda.